CRLF3 plays a key role in the final stage of platelet genesis and is a potential therapeutic target for thrombocythemia.

The process of platelet production has so far been understood to be a 2-stage process: megakaryocyte maturation from hematopoietic stem cells followed by proplatelet formation, with each phase regulating the peripheral blood platelet count. Proplatelet formation releases into the bloodstream beads-on-a-string preplatelets, which undergo fission into mature platelets. For the first time, we show that preplatelet maturation is a third, tightly regulated, critical process akin to cytokinesis that regulates platelet count. We show that deficiency in cytokine receptor-like factor 3 (CRLF3) in mice leads to an isolated and sustained 25% to 48% reduction in the platelet count without any effect on other blood cell lineages. We show that Crlf3-/- preplatelets have increased microtubule stability, possibly because of increased microtubule glutamylation via the interaction of CRLF3 with key members of the Hippo pathway. Using a mouse model of JAK2 V617F essential thrombocythemia, we show that a lack of CRLF3 leads to long-term lineage-specific normalization of the platelet count. We thereby postulate that targeting CRLF3 has therapeutic potential for treatment of thrombocythemia

Dynamics of spontaneous activity in the fetal macaque retina during development of retinogeniculate pathways

Correlated spontaneous activity in the form of retinal waves has been observed in a wide variety of developing animals, but whether retinal waves occur in the primate has not been determined previously. To address this issue, we recorded from isolated retinas using multielectrode arrays at six fetal ages: embryonic day 51 (E51), E55, E60, E67, E71, and E76. These recordings revealed that the fetal monkey retina is essentially silent at E51 and E55, with only few cells firing on rare occasions and without any obvious spatial or temporal order. Because previous work has shown that the magnocellular and parvocellular subdivisions of the dorsal lateral geniculate are selectively innervated during this early period, our results suggest that this process is unlikely to be regulated by retinal activity. Highly structured retinal waves were first observed at E60, \u3e1 week before the segregation of eye-specific retinal dorsal lateral geniculate nucleus projections commences. The incidence of such waves decreased rapidly and progressively during the developmental period (E67-E76) when segregated eye-specific projections become established. Our findings indicate that retinal waves first occur in the fetal monkey at a remarkably early stage of development, \u3e100 d before birth, and that this activity undergoes rapid changes in salient properties when eye-specific retinogeniculate projections are being formed. Copyright © 2006 Society for Neuroscience

Stimulus contrast and retinogeniculate signal processing

Neuronal signals conveying luminance contrast play a key role in nearly all aspects of perception, including depth perception, texture discrimination, and motion perception. Although much is known about the retinal mechanisms responsible for encoding contrast information, relatively little is known about the relationship between stimulus contrast and the processing of neuronal signals between visual structures. Here we describe simultaneous recordings from monosynaptically connected retinal ganglion cells and lateral geniculate nucleus (LGN) neurons in the cat to determine how stimulus contrast affects the communication of visual signals between the two structures. Our results indicate that 1) LGN neurons typically reach their half-maximal response at lower contrasts than their individual retinal inputs, and 2) LGN neurons exhibit greater contrast-dependent phase advance (CDPA) than their retinal inputs. Further analyses suggests that increased sensitivity relies on spatial convergence of multiple retinal inputs, while increased CDPA is achieved, in part, on temporal summation of arriving signals

Stimulus Contrast and Retinogeniculate Signal Processing.

Neuronal signals conveying luminance contrast play a key role in nearly all aspects of perception, including depth perception, texture discrimination, and motion perception. Although much is known about the retinal mechanisms responsible for encoding contrast information, relatively little is known about the relationship between stimulus contrast and the processing of neuronal signals between visual structures. Here, we describe simultaneous recordings from monosynaptically connected retinal ganglion cells and lateral geniculate nucleus (LGN) neurons in the cat to determine how stimulus contrast affects the communication of visual signals between the two structures. Our results indicate that: (1) LGN neurons typically reach their half-maximal response at lower contrasts than their individual retinal inputs and (2) LGN neurons exhibit greater contrast-dependent phase advance (CDPA) than their retinal inputs. Further analyses suggests that increased sensitivity relies on spatial convergence of multiple retinal inputs, while increased CDPA is achieved, in part, on temporal summation of arriving signals